A common feature of neurodegenerative diseases is the aberrant and excessive loss of neurons by activation of apoptosis. Numerous molecules involved in the promotion or inhibition of neuronal apoptosis have been identified and these are being organized as components of signal transduction pathways. This proposal focuses on sirtuins, a family of deacetylating enzymes that are the subject of intense investigation because of their role in a variety of different biological processes including the regulation of neurodegeneration. Like some other labs, we have found that one of the sirtuin proteins, SIRT1, protects neurons from apoptosis. But contrary to the conclusions of previous studies, we find that neuroprotection by SIRT1 is mediated by a novel, non-catalytic mechanism. The objective of the proposal is to use a multi- pronged approach to elucidate the novel mechanism by which SIRT1 exerts its neuroprotective action. The specific aims are - (1) to identify the region within SIRT1 that mediates neuroprotection, (2) to identify downstream targets and mechanism of SIRT1 action in neurons, and (3) to identify SIRT1-interacting proteins in neurons using mass-spectrometry. The long term goal of this research is to develop novel and effective strategies to prevent cell death in neurodegenerative pathologies. PUBLIC HEALTH RELEVANCE: Neurological diseases disrupt the quality of life for patients and cost society billions of dollars annually. While symptomatic treatments are available for many neurological diseases, a cure is not presently available. Identifying molecules that regulate neuronal survival and understanding the mechanism by which they act would lead to the development of more effective therapeutic strategies. Our proposal focuses on SIRT1, a protein that protects neurons from degeneration. It is our hope that the results from the studies we propose will shed insight into how SIRT1 exerts its neuroprotective effect and thus provide novel strategies to prevent neuronal loss in neurodegenerative conditions.